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WO1997008312A1 - Chevauchement du gene pms2 par le gene $i(jtv1) d'origine humaine - Google Patents

Chevauchement du gene pms2 par le gene $i(jtv1) d'origine humaine Download PDF

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Publication number
WO1997008312A1
WO1997008312A1 PCT/US1996/013598 US9613598W WO9708312A1 WO 1997008312 A1 WO1997008312 A1 WO 1997008312A1 US 9613598 W US9613598 W US 9613598W WO 9708312 A1 WO9708312 A1 WO 9708312A1
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hpms2
leu
ser
pro
gene
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WO1997008312A9 (fr
WO1997008312B1 (fr
Inventor
Bert Vogelstein
Kenneth W. Kinzler
Nicholas C. Nicolaides
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Johns Hopkins University
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Johns Hopkins University
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Priority to AT96930577T priority Critical patent/ATE252638T1/de
Priority to JP9510440A priority patent/JPH11511323A/ja
Priority to DE69630458T priority patent/DE69630458D1/de
Priority to EP96930577A priority patent/EP0852620B1/fr
Publication of WO1997008312A1 publication Critical patent/WO1997008312A1/fr
Publication of WO1997008312B1 publication Critical patent/WO1997008312B1/fr
Publication of WO1997008312A9 publication Critical patent/WO1997008312A9/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • HNPCC Hereditary Nonpoiyposis Colon Cancer
  • CRC colorectal cancer
  • a hereditary defect in mismatch repair is likely to be responsible for both the microsatellite instability and tumor susceptibility in HNPCC patients (Parsons et.al., 1993; Umar, et.ai., 1994).
  • Four genes that participate in mismatch repair hMSH2, KMLHl, hPMSl, and hPMS2 have been discovered and shown to be mutated in the germ-line of HNPCC patients (Fishel, et.al., 1993; Leach et.aL, 1993; Palombo. et.aL, 1994; Bronner et.al., 1994; Papadopouios et.al., 1994; Nicolaides et.a , 1994).
  • Mismatch repair is initiated with the binding of MutS-related proteins to mismatched basepairs, and continues with the binding of mutL-related proteins to the mutS-DNA complex (reviewed in Modrich, 1995). Other components are then recruited to excise the DNA strand containing the mismatch and replace it with the correct nucieotides.
  • Human mutL-related proteins involved in this pathway have recemly been purified to homogeneity and shown to complement the mismatch repair activity of a human tumor cell line which is deficient in mismatch repair (Li and Modrich, 1994). The complementing activity is present in a heteroduplex that is comprised of a 85 and a 110 kDa protein.
  • a segment of cDNA is provided.
  • the cDNA consists of the sequence of nucleotides shown in Figure 2.
  • a vector comprising the segment of cDNA which consists of the sequence of nucleotides shown in Figure 2 is provided, as well as host cells comprising the vector.
  • composition consists essentially of a protein consisting of the amino acid sequence shown in Figure 2.
  • a composition of protein JTV1 as shown in Figure 1 is provided.
  • the composition is free of other human proteins.
  • a segment of cDNA is provided which segment encodes the amino acid sequence of JTV1 protein shown in Figure 2.
  • cDNA probes are also provided by the present invention. The cDNA portion of said probes consists of between 15 and 1176 contiguous nucleotides of the sequence shown in SEQ ID NO:l. BRIEF DESCRIPTION OF THE DRAWINGS
  • Figure 1 shows the sequence of the 5' region of hPMS2 and predicted coding region.
  • the arrow indicates the 5' end of the previously published cDNA clone.
  • the presumptive initiating methionine is underlined.
  • Figure 2 shows the sequence of JTV1.
  • the sequence has been deposited in Genbank, accession number U24169.
  • the presumptive initiating methionine is underlined.
  • Figure 3 demonstrates the genomic localization of JTVI.
  • the genomic localization oihPMS2 and JTVI were confirmed by screening somatic-cell hybrids containing various regions of human chromosome 7.
  • Lane 1, GM10791 contains entire chromosome 7 in a Chinese hamster ovary (CHO) background;
  • NA11440 contains 7pter> 7p22 in a CHO background;
  • lane 3, Ru-Rag4-13 contains 7cen-7pter in a murine background;
  • lane 4, 4AF1/106/K015 contains 7cen-qter in a murine background;
  • lane 5, GM05184.17 contains 7q21.2-qter in a CHO background;
  • lane 6, 2068Rag22-2 contains 7q22-qter in a murine background;
  • lane 9, CHO genomic DNA e.g.
  • Figure 4 demonstrates the mapping of transcriptional start sites of hPMS2 and JTVI. Sequence of the genomic region containing the 5' ends of the two genes is shown. The sequence is numbered in respect to codon 1 of hPMS2. Lower case letters denote inrronic sequence of JTVI (from nt -479 to -833) and hPMS2 (from +24 to + 108). Arrows indicate the 5' ends of hPMS2 (sense strand) and of JTVI (antisense strand) cDNA clones. The underlined ATG codons indicate the predicted initiating methionines for hPMS2 (at nt + 1 on the sense - A .
  • Figure 5 shows the expression of hPMS2 and JTVI.
  • RNA from various tissues was incubated with reverse transcriptase (RT+) or in control reactions without reverse transcriptase (RT-).
  • the cDNA was used as template for PCR with primers specific for hPMS2 (A) and JTVI (B).
  • RT-PCR products were separated by polyacrylamide gel electrophoresis. DETADLED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • JTVI JTVI cDNA sequence
  • a segment of cDNA according to the present invention refers to a contiguous stretch of deoxyribonucleotides which have a sequence as obtained upon reverse transcriptase of an RNA transcript. Such segments do not contain introns.
  • the segment may be an isolated molecule or it can be covalently joined to other nucleic acid sequences.
  • the segment may, for example, be replicated as part of a vector, such as a plasmid, virus, or minichromosome.
  • the vector may be replicated within a host cell, such as a cell transformed by a recombinant DNA molecule.
  • the host cell may be used to produce JTVI protein.
  • JTVI sequences can also be used to study regulation of expression of JTVI sequences, for example by subjecting the host cell to various agents which may or may not affect the expression.
  • DNA sequence is discussed with particularity herein, it is well within the skill of the an to make small mutations, such as single nucleic acid substitutions of one of the other three nucleic acid bases, at any of the positions of the sequence.
  • single base deletions or single base insertions to study the effect upon protein structure and function. If JTVI is produced in a recombinant host cell which is not human, a composition of JTVI protein will be produced which is free of other human proteins.
  • JTVI protein is isolated from naturally producing cells, or from human host cells, then the protein can be purified, for example, using antibodies which are raised against an immunogen comprising JTVI amino acid sequence. Any other means of purification known in the an can be used, as is desired.
  • DNA molecules can be made having different nucleotide sequences from that disclosed in SEQ ID NO:l, but which still encode the JTVI protein as disclosed in SEQ ID NO:2. Using the known coding relationships between codons and amino acids and the disclosed amino acid sequence, numerous other sequences can be readily designed and produced. Such DNA molecules are within the contemplation of the subject invention.
  • cDNA probes can be used for hybridization studies. Typically they are labeled with a detectable marker, such as a radiolabel or a fluorescent moiety, although they need not be.
  • the cDNA probes of the subject invention consist of at least 15 contiguous nucleotides of the sequence shown in SEQ ID NO:l. If greater specificity is desired, larger molecules of 18, 20, 25, or 30 nucleotides can be used, up to a maximum of the entire sequence of 1176 nucleotides.
  • JTVI cDNAs can be used as probes to detect deletions in chromosome 7. Due to the overlapping promoter regions, large deletions oi JTVI would also be expected to affect PMS2 expression, leading to Hereditary Non-Polyposis Colorectal Cancer (HNPCC). JTVI cDNA can be used in chromosome mapping. It can also be used to assay activity or competence of the PMS2 promoter region. The presence of JTVI transcripts or JTVI protein suggests that the PMS2 promoter is intact. If the PMS2 promoter is intact and PMS2 products are absent, a structural defect in the coding region is indicated.
  • HNPCC Hereditary Non-Polyposis Colorectal Cancer
  • JTVI sequences can be used to guide homologous recombination at the PMS2 locus. For example, where a PMS2 mutation is present and therapeutic replacement with a wild-type gene is desired, PMS2 sequences can be used to provide an adjacent region of homology. Similariy, it may be desirable to target other genes to the region adjacent to PMS2. JTVI sequences can be used to flank such other genes, providing one or more regions of homology. If insertion of other genes is desired between the JTVI and the PMS2 sequences, again, this can be accomplished using the identified sequences as homology units for homologous recombination.
  • Two cDNA libraries were screened with a probe containing nt +24 to +136 of hPMS2 generated by PCR using Pl clone 53 as template and the primers H and I (Table 1).
  • a human small intestine random-primed cDNA library in ⁇ GTIO (Clontech) and a HeLa oligo-dT primed cDNA library in ⁇ ZAPII (Stratagene) were screened as described except hybridizations were carried out at 68°C and filters were washed at 65°C for 0.5 hrs (Kinzler and Vogelstein, 1989). Following plaque purification, the EcoRI inserts from the small intestine library were subcloned into pBluescript vector, while the HeLa cDNA inserts were rescued as phagemids following the manufacturer's protocol (Stratagene).
  • One clone was isolated from the random-primed small intestine library, and this contained nt -14 to nt +1668 of hPMS2.
  • Two clones were isolated from the oligo-dT primed HeLa cDNA library. The clones began at nt -53 and ended at either nts +2722 or +2749.
  • the HeLa cDNA library was also screened with a 430 bp probe from the 5' genomic region of hPMS2, containing nt -414 to +16, generated by PCR from Pl clone 53 using primers D (Table 1) and O (Table 2). The same two clones were identified, as expected.
  • JTVI twelve other overlapping clones were found and appeared to represent a different transcript, named JTVI ( Figure 2). These twelve cDNAs were approximately 1.2 kb in length and were sequenced in their entirety. All twelve ended with a polyA tract (assumed to be the 3' end) and were identical for 1.2 kb upstream. The 5' ends were located within 38 bp of each other. Comparison with hPMS2 indicated that JTVI was transcribed from the opposite strand.
  • the length of one clone representative of JTVI was 1233 bp and encoded an open reading frame (ORF) of 936 bp ( Figure 2).
  • the first methionine within this ORF was designated codon 1 ( Figure 2) and was preceded by an in-frame termination codon 66 bp upstream. This methionine had a reasonable match to the Kozak translation initiation consensus (Kozak, 1986).
  • the 3' end contained a polyadenylation signal (AAUAAA) starting at nucleotide 1086 followed by a polyA tail.
  • the transcript was predicted to encode a polypeptide of 312 amino acids, with a molecular weight of 34.5 kda. Searches of nucleotide and peptide sequence databases showed that this was a novel gene, with limited homology to the glutathione S-transferase gene family. 97/08312 PC17US96/13598
  • the hPMS2 locus was previously mapped to chromosome 7p22 by FISH using Pl clone 53 (Nicolaides et.al., 1994). Because multiple hPMS2- ⁇ cla.te ⁇ genes are located on the long arm of chromosome 7 and have conserved 5' regions
  • PCR primers were chosen from the 3' untranslated region of hPMS2 and JTVI and shown to amplify genomic DNA.
  • hPMS2 primers J and K yielded a 121 bp product and JTVI primers Q and R yielded a 134 bp product.
  • PCR products for both genes were formed in those DNAs containing the 7p22 region: lines
  • GM10791 containing the entire human chromosome 7
  • NA11440 (Coriell
  • RT-PCR of the 5' end of hPMS2 was performed using a common antisense primer (I) and the sense primers (A-F) described in Table 1.
  • RT-PCR mapping of the 5' end of JTVI was done using a common antisense primer P and the sense primers L-O as described in Table 2.
  • RACE rapid amplification of cDNA ends, Frohman, et.al., 1988
  • hPMS2 was performed using sequential antisense primers I and G (Table 1) following the manufacturer's protocol (Clontech).
  • RACE analysis of JTVI was done using the antisense primer P (Table 2).
  • Amplification products were cloned into a T-tailed vector (InVitrogen) and sequenced using SP6 and T7 primers. Amplifications were done at 95 °C for 30 sec, 56°C for 1.5 min., and 70°C for 1.5 min for 35 cycles. Reaction products were separated by electrophoresis in 6% nondenaturing polyacrylamide gels.
  • Figure 4 shows the sequence of the genomic region containing the transcriptional initiation sites of both hPMS2 and JTVI, numbered as in Figure 1 with respect to hPMS2.
  • the 5' ends of hPMS2 cDNA clones are marked with arrowheads on the top strand.
  • One clone began at nt -14, one at nt -24, and two at nt -53.
  • RACE products were generated from adult brain, leukocyte, and placenta mRNA.
  • an antisense primer corresponding to nt +116 to + 136 multiple bands with approximately 160 to 191 bps were observed in addition to less intense bands of up to 550 bp.
  • JTVI The 5' termini of JTVI showed a heterogeneous pattern like that of hPMS2.
  • the 5' ends of the 12 cDNA clones are indicated by arrowheads on the bottom strand in figure 4. They were located 73 to 113 nt 73 upstream of codon 1 of JTVI, which co ⁇ esponded to nt -271 to -232 of hPMS2.
  • RACE confirmed the cDNA results in that the majority of products generated using an antisense primer P co ⁇ esponding to JTVI nt + 157 were 230 to 270 bp.
  • RT-PCR analysis was performed with antisense primer P and several sense primers (L-O) listed in Table 2.
  • PCR products were found with sense primers whose 5' ends were at -8, -23, and -111, (primers L,M, and N) but not with a sense primer O whose 5' end was at nt -360 with respect to JTVI, nt + 1.
  • the latter primer was not defective, as a genomic segment could be successfully amplified with it.
  • Transcripts of hPMS2 had heterogeneous but collinear 5' termini, containing 11 to 415 nt of presumably untranslated sequence.
  • the transcripts contained an in-frame stop codon upstream of the presumptive initiating methionines (Figure 1), making the originally described methionine the most likely translation initiator. Because no other upstream coding regions of hPMS2 appeared to exist, the size discrepancy between that predicted from the hPMS2 sequence and the 110 kDa hPMS2 protein identified by Li and Modrich is likely due to post-transcriptional modifications or alternative internal exons.
  • HUMDUG and DHFR do not overlap, as is true for hPMS2 and JTVI. It will be of interest to determine whether other mismatch repair genes are arranged in a head to head fashion with a contiguous gene and if JTVI is involved in DNA replication or repair.
  • hPMS2 and JTVI The expression of hPMS2 and JTVI was analyzed in a variety of mRNA samples prepared from human tissues. RT-PCR was performed on cDNA templates derived from adult brain, leukocytes, kidney, large intestine, colon, salivary gland, lung, testes and prostate using primers J and K for hPMS2 and primers Q and R for JTVI (Tables 1 and 2). Both genes were expressed in all tissues tested ( Figure 5).
  • Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eucaryotic ribosomes. Cell 44:283-292.
  • Genomic instability in repeated sequences is an early somatic event in colorectal tumourigenesis that persists after transformation. Nature Genet. 6:273-281.
  • MOLECULE TYPE DNA (genomic)

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Abstract

Le gène hPMS2 code une protéine qui intervient dans la réparation des mésappariements de l'ADN et subit une mutation chez des patients d'un sous-ensemble, atteints de cancer colique héréditaire sans polypose (HNPCC). A la séquence d'ADNc du gène hPMS2 précédemment publiée, il manque un codon de terminaison amont, interne au cadre, et précédant la présumée méthionine d'initiation. Afin d'étudier plus avant l'extrémité 5' de la région codante du gène hPMS2, nous avons isolé des clones d'ADNc supplémentaires, des produits de réaction RT-PCR, ainsi que le segment génomique 5' correspondant du locus du gène hPMS2. On a trouvé que les produits de transcription du gène hPMS2 avaient des extrémités 5' hétérogènes mais colinéaires, l'une d'entre elles étant contenue dans un codon de terminaison, interne au cadre, et précédant la méthionine d'initiation. En outre, on a trouvé qu'un gène codant un polypeptide de 34,5 kDa pouvait effectuer une initiation par transcription à l'intérieur du gène hPMS2 à partir du brin opposé.
PCT/US1996/013598 1995-08-24 1996-08-26 Chevauchement du gene pms2 par le gene $i(jtv1) d'origine humaine Ceased WO1997008312A1 (fr)

Priority Applications (4)

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AT96930577T ATE252638T1 (de) 1995-08-24 1996-08-26 Das humane jtvi-gen überlappt mit dem pms2-gen
JP9510440A JPH11511323A (ja) 1995-08-24 1996-08-26 ヒトｊｔｖ１遺伝子はｐｍｓ２遺伝子と部分的に重なる
DE69630458T DE69630458D1 (de) 1995-08-24 1996-08-26 Das humane jtvi-gen überlappt mit dem pms2-gen
EP96930577A EP0852620B1 (fr) 1995-08-24 1996-08-26 Chevauchement du gene humain pms2 par le gene jtv1

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US08/518,862 US5843757A (en) 1995-08-24 1995-08-24 Human JTV1 gene overlaps PMS2 gene
US08/518,862 1995-08-24

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CA (1) CA2229789A1 (fr)
DE (1) DE69630458D1 (fr)
WO (1) WO1997008312A1 (fr)

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WO2002040499A1 (fr) * 2000-11-14 2002-05-23 Morphotek Inc. Methode permettant de produire des antigenes genetiquement modifies
US6656736B2 (en) 2000-02-23 2003-12-02 The Johns Hopkins University Methods for generating hypermutable yeast
US6737268B1 (en) 2000-11-14 2004-05-18 Morphotek, Inc. Method for generating genetically altered antigens
EP1454628A3 (fr) * 2003-03-03 2004-10-13 Seoul National University Industry Foundation Utilisation médicale de p38/JTV-1
US6825038B2 (en) 2000-05-12 2004-11-30 The Johns Hopkins University Method for generating hypermutable organisms
US6900370B2 (en) 2000-02-18 2005-05-31 John Hopkins University Method for generating hypermutable plants
US7026119B2 (en) 2000-02-11 2006-04-11 Morphotek, Inc. Methods for generating hypermutable microbes
US7297837B1 (en) 1998-04-14 2007-11-20 The John Hopkins University Method for generating hypermutable organisms
EP2566499A4 (fr) * 2010-05-04 2014-08-06 Atyr Pharma Inc Découverte innovante de compositions thérapeutiques, diagnostiques et à base d'anticorps liées à des fragments protéiques de complexe multi-arnt synthétase p38

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US6844152B1 (en) * 2000-09-15 2005-01-18 Promega Corporation Detection of microsatellite instability and its use in diagnosis of tumors
US7070940B2 (en) * 2002-07-18 2006-07-04 Aventis Pharma S.A. Method for determining the ability of a compound to modify the interaction between parkin and the p38 protein
US20090075378A1 (en) 2007-02-20 2009-03-19 Anaptysbio, Inc. Somatic hypermutation systems

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NICOLAIDES ET AL.: "Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.", NATURE, vol. 371, 1 September 1994 (1994-09-01), pages 75 - 80, XP002021621 *
NICOLAIDES N.C. ET AL.: "Analysis of the 5' region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene.", GENOMICS, vol. 29, 20 September 1995 (1995-09-20), pages 329 - 334, XP000615435 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7829338B2 (en) 1998-04-14 2010-11-09 The Johns Hopkins University Method for generating hypermutable organisms
US7297837B1 (en) 1998-04-14 2007-11-20 The John Hopkins University Method for generating hypermutable organisms
US7026119B2 (en) 2000-02-11 2006-04-11 Morphotek, Inc. Methods for generating hypermutable microbes
US7892832B2 (en) 2000-02-11 2011-02-22 The Johns Hopkins University Methods for generating hypermutable microbes
US7695969B2 (en) 2000-02-11 2010-04-13 The Johns Hopkins University Methods for generating hypermutable microbes
US6900370B2 (en) 2000-02-18 2005-05-31 John Hopkins University Method for generating hypermutable plants
US7704689B2 (en) 2000-02-18 2010-04-27 The Johns Hopkins University Method for generating hypermutable plants
US8110356B2 (en) 2000-02-18 2012-02-07 The Johns Hopkins University Method for generating hypermutable plants
US6656736B2 (en) 2000-02-23 2003-12-02 The Johns Hopkins University Methods for generating hypermutable yeast
US7514216B2 (en) 2000-02-23 2009-04-07 The Johns Hopkins University Methods for generating hypermutable yeast
US7759121B2 (en) 2000-02-23 2010-07-20 The John Hopkins University Methods for generating hypermutable yeast
US6921666B2 (en) 2000-02-23 2005-07-26 The Johns Hopkins University Methods for generating hypermutable yeast
US7319036B2 (en) 2000-05-12 2008-01-15 The Johns Hopkins University School Of Medicine Method for generating hypermutable organisms
US6825038B2 (en) 2000-05-12 2004-11-30 The Johns Hopkins University Method for generating hypermutable organisms
US6737268B1 (en) 2000-11-14 2004-05-18 Morphotek, Inc. Method for generating genetically altered antigens
WO2002040499A1 (fr) * 2000-11-14 2002-05-23 Morphotek Inc. Methode permettant de produire des antigenes genetiquement modifies
EP1454628A3 (fr) * 2003-03-03 2004-10-13 Seoul National University Industry Foundation Utilisation médicale de p38/JTV-1
EP2566499A4 (fr) * 2010-05-04 2014-08-06 Atyr Pharma Inc Découverte innovante de compositions thérapeutiques, diagnostiques et à base d'anticorps liées à des fragments protéiques de complexe multi-arnt synthétase p38
US9062302B2 (en) 2010-05-04 2015-06-23 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of p38 multi-tRNA synthetase complex
US9404104B2 (en) 2010-05-04 2016-08-02 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of P38 multi-tRNA synthetase complex
AU2011248101B2 (en) * 2010-05-04 2016-10-20 Atyr Pharma, Inc. Innovative discovery of therapeutic, diagnostic, and antibody compositions related to protein fragments of p38 multi-tRNA synthetase complex

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EP0852620A1 (fr) 1998-07-15
JPH11511323A (ja) 1999-10-05
ATE252638T1 (de) 2003-11-15
US5843757A (en) 1998-12-01
CA2229789A1 (fr) 1997-03-06
EP0852620B1 (fr) 2003-10-22
DE69630458D1 (de) 2003-11-27

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